Still disease in adults

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Still's disease in adults or aosd (Engl. A dult- o n set S till's D isease ) is the progressive form of Still's disease in adults and is one of the rare autoinflammatory diseases (in children and adolescents is known as the systemic juvenile idiopathic arthritis , SJIA ). The disease usually begins between the ages of 15 and 40. Two age peaks can be observed for the onset of the disease: between 15 and 25 years and between 36 and 46 years. Ten percent of those affected are older than 50 when the disease begins.

Epidemiology

AoSD is a very rare disease that occurs worldwide. It is estimated that one in one million people in Europe get it. Men and women are equally affected. However, these are older epidemiological studies ; current data are not yet available (as of December 2019).

Pathogenesis

The pathogenesis of the disease is not yet known in detail, but homology between SJIA and AoSD has been proven. AoSD is one of the non-familial, sporadic systemic autoinflammatory diseases. The descriptions of the mechanisms that lead to the pathogenesis of AoSD are so far purely hypothetical in nature. The pro-inflammatory cascade probably plays an important role in this.

AoSD is a systemic inflammatory disease, the manifestation of which includes a wide range of symptoms and possible complications. According to the current state of research, AoSD leads to an intensive activation of the innate immune cells and thus to a pathological overproduction of various pro-inflammatory cytokines such as interleukin- 1, interleukin-6, interleukin-17, interleukin-18 and tumor necrosis factor (TNF) . It is assumed that specific signal substances such as PAMPs ( pathogen-associated molecular patterns ) or DAMPs ( damage-associated molecular patterns ) are released in the patient's body. These messenger substances reach the neutrophil granulocytes via toll-like receptors . As a result, different inflammasomes are activated. This signal cascade leads to an overproduction of active interleukin-1β. This mechanism appears to be crucial for the pathogenesis of AoSD. A group of proteins, the so-called alarmins , also seem to be involved in the development of the disease.

In addition, defects in the body's own inflammatory regulatory processes seem to play a role in the development of the disease. Patients may be deficient in regulatory T cells or in the production of interleukin-10 by natural killer cells . An insufficient breakdown of certain lipid mediators could also be involved in the pathological inflammatory reactions in AoSD.

The inflammatory reactions associated with AoSD can be triggered by infections, for example. Bacteria and viruses use PAMPs to trigger alarm signals within the immune system . This can trigger the overreaction of the immune system as well as the pathological inflammatory reactions associated with AoSD.

Symptoms

AoSD has four cardinal symptoms : fever , joint pain , skin rashes and a significantly increased number of leukocytes (over 10,000 per microliter) and neutrophils (over 80 percent) in the blood. The patients suffer relapses of fever of up to 40 ° C, which mainly occur in the evening hours. It is characteristic here that the fever occurs suddenly and increases rapidly. The health of those affected is rapidly deteriorating.

An inflammation of the throat can also be an initial symptom of AoSD. As the disease progresses, a clear increase in leukocytes in the blood can be detected. In addition, patients suffer from severe joint pain, mainly in the knee , elbow , ankle and wrist joints . Pink to red, blotchy rashes often develop on the skin of those affected during the fever attacks, which disappear again when the fever is removed. Patients have swollen lymph nodes and their spleen and liver may enlarge. Possible complications include inflammatory changes in the joints, including stiffening. Complications that affect vital organs such as the brain , heart and lungs are less common . Brain involvement manifests itself in epileptic seizures , paralysis or meningitis . If the heart is affected, pericarditis can develop . Lung involvement manifests itself in pneumonia and pleurisy . The AoSD runs in spurts.

Other possible manifestations of the disease can include swallowing disorders , muscle pain, and blood clotting disorders .

Macrophage activation syndrome (MAS) is a life-threatening complication of Still's syndrome, both in children and adults .

diagnosis

AoSD is a diagnosis of exclusion . It is only established after autoimmune, haematological and infectious diseases such as collagenoses , neoplasias and endocarditis can be ruled out. The diagnosis of AoSD is usually difficult because it is a rare disease that is not part of the daily clinical picture in a doctor's practice. In addition, the symptoms at the beginning of the disease are unspecific and can therefore indicate other more common diseases. The suspected diagnosis is made based on the cardinal symptoms of AoSD. However, their type and characteristics differ from patient to patient. So far, there have not been any clear laboratory values ​​that specifically indicated an AoSD.

Affected patients have a significantly increased number of leukocytes in the blood. In addition, elevated liver values ​​can be found. Serum ferritin can be a possible indicator . High serum ferritin levels indicate activation of the macrophages and abnormally high levels of cytokines. However, studies have shown that serum ferritin also has an insufficient predictive and diagnostic value in AoSD.

Other possible biomarkers for AoSD have been investigated, but are not yet part of current diagnostic practice. There are indications that with a systemic manifestation of the disease, the concentrations of interleukin-1, interleukin-6 and interleukin-18 are significantly increased. These interleukins could act as possible diagnostic markers in systemic AoSD.

So far, so-called major and minor diagnostic criteria have been defined for AoSD:

Major criteria Minor criteria Exclusion criteria
Fever over 39 ° C that lasts for at least a week Sore throat Infections
Fleeting salmon-colored rashes typical of AoSD Abnormally high liver function tests Rheumatic diseases of another kind
Pain in joints and muscles that lasts for over two weeks Lymph nodes swollen, enlarged spleen Malignant tumor
Abnormally high white blood cell count

> 10,000 / µl

Test for antinuclear antibodies and rheumatoid factors shows negative results.


Course and prognosis

AoSD progresses individually differently, so only very limited statements can be made about the course of the disease . The course of the disease was examined in different studies, but these are individual case studies with a few patients.

The disease can have a monocyclic course. This is the case for 19 to 44 percent of AoSD patients. This is usually self-limiting and disappears by itself without the administration of medication. The systemic manifestation of the disease takes several weeks. If the patient feels pain, anti-inflammatory nonsteroidal anti-inflammatory drugs (NSAIDs)  or immunomodulatory drugs can be given.

AoSD can also progress in several recurrent attacks. Months or even years after a treated flare-up, another flare-up can occur. The affected patients usually had their first flare-up in their youth in the form of SJIA, which could be successfully treated. Years later, in later adulthood, another episode follows. The recurrences represent a combination of systemic and joint inflammation. The disease has such a recurring polycyclic course in 10 to 44 percent of affected patients.

The most common course of the disease (in 35 to 67 percent of those affected) is the chronically progressive course. This form is characterized by chronic persistent inflammation and joint damage. Systemic inflammation occurs again and again in regular cycles.

therapy

Treatment options for AoSD used to be limited to anti-inflammatory pain relievers and glucocorticoids . However, these therapies have been found to be moderately effective, especially for severe forms of the disease. In 30 to 40 percent of patients, the disease was very difficult or impossible to control with the help of glucocorticoids and NSAIDs.

More modern treatment options include the administration of biologics one, which are approved to treat aosd (z. B. canakinumab or anakinra ). The use of anakinra is particularly indicated in those affected who have active systemic features of moderate to high disease activity or in patients with persistent disease activity after treatment with NSAIDs or glucocorticoids and can be used as first-line monotherapy or in combination with other anti-inflammatory drugs and basic therapeutic DMARDs ( disease-modifying anti-rheumatic drugs) are used. Canakinumab is indicated for the treatment of active Still syndrome in patients who have not responded adequately to previous therapies with NSAIDs and systemic corticosteroids in monotherapy or in combination with the DMARD methotrexate .

outlook

At AoSD, the treat-to-target principle is the strategically preferred approach of choice. This is a drug therapy that targets specific molecules in the body. There is current evidence that targeted inhibition of interleukin-1, interleukin-6, interleukin-18, and TNF can inhibit the inflammatory responses that occur in AoSD. Targeted TNF, interleukin-1, interleukin-6 and interleukin-18 inhibitors could be used in the future.

Individual evidence

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